Cyclohexanols



Patented Oct. 20, 1953 UNITED STATES PATENT OFFICE 2,656,395CYCLOHEXANOLS John A. Hogg, Jerome Korman, William Bradley Reid, Jr.,and Alan H. Nathan, Kalamazoo, Mich., assignors to The Upjohn Company,Kalamazoo, Mich., a corporation of Michigan No Drawing. ApplicationFebruary 24, 1951,

Serial No. 212,673

9 Claims. (01. 260563) This invention relates to 1-methy1-2-(B-diwherein R is a hydrocarbon radical containing from one to seven carbonatoms, inclusive, such as the methyl, ethyl, propyl, isopropyl, butyl,isobutyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, phenyl and benzyl radicals and the like. In the compounds ofthis invention the radicals designated B may be the same or differenthydrocarbon radicals. The group RO- is herein termed a hydrocarbonoxygroup, and the preferred embodiment of R is methyl.

The products of this invention, when subjected to dehydration, yield 1methyl-Z-(p-disubstituted aminoethyl) 4 hydrocarbonoxycyclohexenes whichare more fully disclosed and claimed in our copending application,Serial No. 212,674, filed February 24, 1951.

Addition of cyanogen bromide to the l-methyl- 2 (B disubstitutedaminoethyD-4-hydrocarbonoxycyclohexenes described hereinbefore anddecomposition of the resulting quaternary salt give 1-methy1-2-(pbromoethyl) -4-hydrocarbonoxycyclohexenes which are more fullydisclosed and claimed in the copending application of John A. Hogg,Serial 212,675, filed February 24, 1951.

The compounds of the present invention can be prepared starting with apara-hydrocarbonoxyphenol (for example, a monoalkyl ether ofhydroquinone) having the formula:

wherein R is a hydrocarbon radical as specified in the foregoingdefinition of R. Such compounds readily react with three molecules ofhydrogen in the presence of a nickel catalyst at temperatures betweenapproximately and approximately 300 degrees centigrated to yield thecorresponding saturated compound, a para-hydrocarbonoxycyclohexanolhaving the formula:

which can be oxidized to a para-hydrocarbonoxycyclohexanone having theformula:

wherein R has the significance hereinbefore assigned, by the use ofpotassium dichromate and sulfuric acid [Helfer, Helv. Chim. Acta, 7, 953(1924)].

The resulting para hydrocarbonoxycyclohexanone is converted, via aClaisen reaction using diethyl oxalate and sodium ethoxide, into a 2ethoxalyl-4-hydrocarbonoxycyclohexanone having the formula:

which is readily converted by means of heat and powdered soft glass intoa 2-carbethoxy-4-hydrocarbonoxycyclohexanone having the formula:

oxycyclohexanone is then condensed in the pres ence of sodium orpotassium with a halogensubstituted tertiary amine having the formulawherein X is a halogen, e. g., chlorine or bromine, and each R is ahydrocarbon radical having the significance hereinbei'ore assigned.fl-diethylaminoethyl chloride is a typical example of such amine.Ordinarily the reaction is conducted in an inert organic solvent, suchas benzene, toluene or xylene, at a temperature between approximately 80and approximately 140 degrees centigrade, and preferably at about thereflux temperature of the solvent employed. The reaction is complete infrom to hours, at the end of which time the product, a2-carbethoxy-2-(c-disubstituted aminoethyl) 4hydrocarbonoxycyclohexanone having the formula;

RO-H

wherein the Rs have the significance herein'before specified, may beisolated in conventional manner, such as by extraction from the organiclayer with dilute acid, e. g., hydrochloric or sulfuric, and subsequentneutralization with alkali, e. g., potassium carbonate or sodiumhydroxide. The crude product is then extracted with a sol vent such asether or benzene and isolated by evaporation of the solvent.

The 2-carbethoxy-2-(fi-disubstituted aminoethyl)-4-hydrocarbonoxycyclohexanone is then decarbalkoxylated, as withhydrochloric or sulfuric acid having a concentration between approximately 10 and approximately 20 percent by weight at a temperaturebetween approximately 80 and approximately 110 degrees centigrade,preferably at about reflux temperature, for a period betweenapproximately 10 and approximately 20 hours, or, alternatively, withbarium hydroxide in alcohol, to produce a 2-(18- disubstitutedaminoethyl)-4-hydrocarbonoxycyclohexanone having the formula:

wherein the Rs have the hereinbefore assigned significance. Afterdecarbalkoxylation, the prodnot is isolated in conventional manner, asby treatment with alkali, extraction with ether, and distillation.

The 2-(p-disubsituted arninoethyl)-4-hydrocarbonoxycyclohexanone istreated with methyl lithium in an organic solvent such as diethyl ether,tetrahydrofuran or N-methylmorpholine to produce, after hydrolysis ofthe intermediate addition product, a l-methyl-2-(c-disubstitutedaminoethyl) 4 hydrocarbonoxycyclohexanol having the formula:

wherein the R's have the hereinbei'ore assigned significance. Thereaction is preferably conducted at the reflux temperature of thesolvent employed, and is ordinarily complete in a period of from 2 to 4hours,

The following examples illustrate typical compounds of the invention andmetho their preparation. It will be understood that changes andmodifications may be adopted, as is obvious to those skilled in the art,Without departing from the spirit or scope of the invention.

PREPARATION l.4-METHYLOXYCYCLOHEXANOL AND OTHER 4-ALKoxYcYoLoHExANoLs Asolution of 500 grams of 4-methoxyphenol (monomethyl ether ofhydroquinone) in 800 milliliters of ethanol was subjected tohydrogenation in the presence of 165 grams (wet weight) of a Raneynickel catalyst prepared by the method of Adkins and Pavlic [J Am. Chem.Soc, 68, 147 (19.46) 1. The initial pressure of the hydrogenation atroom temperature was between approximately 1000 and approximately 1800'pounds per square inch and the final temperature was about 140 degreescentigrade. The total time required for the hydrogenation wasapproximately 2 to 3 hours. After removal of the catalyst and solvent,distillation of the residue gave 445 grams percent) of4-methoxycyclohexanol as a colorless liquid boiling at l04l05 degreescentigrade at a pressure of 13 millimeters of mercury.

In a like manner, 4-ethoxycyclohexanol can be obtained by thehydrogenation of 4-ethoxyphenol (ethyl ether of hydroquinone);4-propoxycyclohexanol can be obtained from 4-propoxyphenol;4-n-butoxycyclohexanol can be obtained from 4- n-butoxyphenol; andi-benzyloxycyclohexanol can be obtained from 4-benzyloxyphenol. These4-alkoxyphenols (ethers of hydroquinone) can be prepared by the methoddescribed by Klarmann, Gatyas and Shternov in J. Am. Chem. Soc, 54, 298(1932).

PREPARATION 2.-4-METHOXYCYCLOHEXANONE AND OTHER 4-ALKoxYoYoLonExANoNEsThe oxidation of e-methoxycyclohexanol (Preparation 1) was carried outaccording to the procedure of Helfer lHelv. Chim. Acta, 7, 953 (1924) Toa solution of grams of potassium. dichromate in grams of sulfuric acidand 400 milliliters of water cooled in an ice-bath was added withvigorous stirring 58.5 grams of 4- methoxycyclohexanol. The temperatureof the reaction mixture rose rapidly to '70 degrees centigrade, and thecolor became brown. Stirring was continued until the temperaturedecreased, after which the product was extracted with ether, isolated byremoval of the ether and purified by distillation; it boiled at 72degrees oentigrade at a pressure of 9 millimeters of mercury.

In a like manner, 4-ethoxycyclohexanone can be obtained by the oxidationof l-ethoxyoyclohexanol; i-propoxycyclohexanone can be obtained from4-propoxycyclohexanol; 4-n-butoxycyclohexanone can be obtained from4-n-butoxycyclohexanol; and 4 benzyloxycyclohexanone can be obtainedfrom 4-benzyloxycyclo'hexanol.

PBEPABATION ;3. -2- cmrrnoxy 4 METHOXYOYCLO- HEXANONE AND OTHERZ-BARBETHOXY-l-ALKOXYCY- GLOHEXANONES The preparation of this compoundwas carried out by the method heretofore described for the preparationof 2-carbethoxycyclohexanone (Snyder, Brooks and Shapiro, Grg.Syntheses, Coll. vol.

II, John Wiley and Sons, New York, 1943, p. 531; Cf. Cook and Laurence,J. Chem. Soc, 1938, 58). To a solution of 46 grams (2 moles) of sodiumin 600 milliliters of absolute ethanol in an ice-salt bath was added at10 degrees centigrade with vigorous stirring a cold solution of 256grams (2 moles) of 4-methoxycyclohexanone (Preparation 2) in 292 grams(2 moles) of ethyl oxalate during a period of to minutes. The mixturewas stirred at ice-bath temperature for about 1 hour and at roomtemperature for about 6 hours, acidified with ice-cold sulfuric acid,and extracted with benzene. After removal of the benzene on asteam-bath, about grams of powdered soft glass was added to the residual2-ethoxalyl-4-methoxycyclohexanone and the mixture was heated to 150degrees centigrade with stirring at a subatmospheric pressure ofapproximately 50 millimeters of mercury until the evolution of carbonmonoxide had ceased. Distillation of the residue gave 132.4 grams (33percent) of 2-carbethoxy-4-methoxycyclohexanone as a heavy yellow oilwhich boiled at 100-105 degrees centigrade at a pressure of 1.2millimeters of mercury.

In a like manner, 2-carbethoxy-4-ethoxycyclohexanone can be obtained bythe ethoxalylation of 4-ethoxycyclohexanone followed by decarbonylationof the 2-ethoxalyl-4-ethoxycyclo hexanone;2-carbethoxy-4-propoxycyclohexanone can be obtained from4-propoxycyclohexanone; 2-carbethoxy-4-n-butoxycyclohexanone can beobtained from 4-n-butoxycyclohexanone; and2-carbethoxy-4-benzyloxycyclohexanone can be obtained from4-benzyloxycyclohexanone.

PREPARATION 4.2-CA.R.BETHOXY-2- (fl-DIETHYLAMINO- ETHYL) -4METHOXYOYCLOHEXANONE AND OTHER 2-CARBETHOXY 2 (fl-DIETHYLAMINOETHYL)-4-AL- KOXYOYC'LOHEXANONES To a suspension of 2.3 grams (0.1 mole) ofsodium sand in 200 milliliters of anhydrous toluene was added dropwisewith stirring a solution of 20.0 grams (0.1 mole) of 2-carbethoxy-4-methoxycyclohexanone (Preparation 3) in 25 milliliters of anhydroustoluene. After the addition, the mixture was heated under reflux withstirring for 3 /2 hours, and then stirred overnight at room temperature.The suspension of the sodio derivative was again heated to boiling andto it was added dropwise, with stirring during 3 hours, a solution of13.6 grams (0.1 mole) of p-diethylaminoethyl chloride in 25 millilitersof anhydrous toluene. After heating under reflux for an additional 7hours, the mixture was cooled and extracted with dilute hydrochloricacid. The acid extract was neutralized with sodium hydroxide solution,saturated with solid potassium carbonate and extracted with ether. Theether extracts were washed with water and dried, and the ether wasevaporated. Distillation of the residue gave a 67 percent yield ofZ-carbethoxy-Z- c diethylaminoethyl) -4-methoxycyclohexanone as a nearlycolorless liquid which boiled at 132- 135 degrees centigrade at apressure of 0.15 millimeter of mercury; n =1.4715.

In a like manner, 2-carbethoxy-2-(fi-di-nbutylaminoethyl)-4-benzyloxycyclohexanone can be obtained by the alkylation of2-carbethoxy-4- benzyloxycyclohexanone with di-n-butylaminoethylchloride, which can be prepared according to the procedures of Barnettet al. [J Am. Chem. Soc, 59, 2248 (1937)] and Blicke and Maxwell [ibid.,64, 428 (1942)]; and 2-carbethoxy-2- (fi-dibenzylaminoethyl) 4 nbutoxycyclohexanone can be obtained by the alkylation of 2-carbethoxy-4-n-butoxycyclohexanone with bibenzylaminoethyl chloridewhich can be prepared according to the procedure of Dupre et al. (J.Chem. Soc, 1949. 500).

PREPARATION 5.2 (18} DmTnmMiNoETHYL)-4- METHOXYOYGLOHEXANONE AND OTHERZ-(fl-DIAL- KY'LAMINOETHYL) -4-ALKoxYcYo:r.0HExANoNms A solution of 17.0grams (0.05 mole) of 2-carbethoxy 2 (B-diethylaminoethyl)-4-methoxycyclohexanone (Preparation 4) in 250 milliliters of 20 percentsulfuric acid was heated under reflux for-18 hours. After cooling, thesolution was neutralized with sodium hydroxide, saturated with solidpotassium carbonate and extracted with ether. The ether extracts wereWashed with water and dried, and the ether was evaporated. Distillationof the residue gave a 76 percent yield of 2- [fi-diethylaminoethyl)-4-methoxycyclohexanone as a colorless oil which boiled at 112-114degrees centigrade at a pressure of 0.8 millimeter of mercury; n=1.4680. The product formed a crystalline salt with oxalic acid whichmelted at 111-112 degrees centigrade.

Analysis (Oxalate) calculated for C15H2706NZ C, 56.76; H, 8.58; N, 4.41.Found: C', 56.89; H, 8.58; N, 4.36.

In a like manner, 2-(fl-di-n-butylaminoethyl) 4-benzyloxycyclohexanonecan be obtained from 2-carbethoxy-2-(B di n butylaminoethyl) -4-benzyloxycyclohexanone; and 2 (5dibenzylaminoethyl)-4-n-butoxycyclohexanone can be obtained from2-carbethoxy-2- (fl-dibenzylaminm ethyl) -4-n-butoxycyclohexanone.

Example 1 .1-methyZ-2- (p-dzethylaminoethyl) 4-methoxycyclohearanol-1 Asolution of methyl lithium in 100 milliliters of anhydrous ether wasprepared from 1.1 grams (0.16 mole) of lithium and 9.9 grams (0.07 mole)of methyl iodide. Excess lithium was removed by filtration under anitrogen atmosphere. To the solution of methyl lithium, under a nitrogenatmosphere, was added dropwise with stirring a solution of 7.0 grams(0.034 mole) of 2-(fi-diethylaminoethyl) -4-methoxycyclohexanone(Preparation 5) When the addition was completed, the mixture was heatedunder reflux for 2 hours, cooled and poured onto ice. The ether layerwas separated, and the aqueous layer, after saturation with solidpotassium carbonate, was extracted with ether. The combined etherfractions were washed with water and dried, and the ether wasevaporated. Distillation of the residue gave an 87 percent yield ofl-methyl 2 (B-diethylaminoethyl) -4-methoxycyclohexanol-l as a colorlessoil which boiled at 90-92 degrees centigrade at a pressure of 0.03millimeter of mercury; n =1.4750.

Analysis calculated for C14H29O2N; C, 69.09; H, 12.01; N, 5.76. Found:C, 68.97; H, 12.48; N, 5.77.

Other examples In a manner similar to that described in Example 1,1-methyl-2-(,B-di-n-butylaminoethyl)- 4-benzyloxycyclohexanol-l can beobtained from 2-(fl-di-n-butylaminoethyl) 4 benzyloxycyclohexanone; and1-methyl-2-(p-dibenzylaminoethyl) -4-n-butoxycyclohexanol-1 can beobtained from 2- (fi-dibenzylaminoethyl) 4 n-butoxycyclohexanone.

We claim:

1. A l-methyl 2-(p-aminoethyl) -4-hydrocarbonoxycyclohexanol having theformula:

in 25 milliliters of anhydrous ether.

1. A 1-METHYL 2-(B-AMINOETHYL)-4- HYDROCARBONOXYCYCLOHEXANOL HAVING THEFORMULA: